Vaccination of non-human primates with self-amplifying mRNA vaccines reveal two distinct immunotypes across major SARS-CoV-2 variants.

Abstract

Abstract mRNA-based vaccines have proven among the most efficacious vaccines against COVID-19. Recent SARS-CoV-2 Delta waves and the emergence of the Omicron variant have demonstrated the necessity of booster doses to a two-dose priming regimen to maintain efficacy against these variants. Global demand for primary mRNA vaccination is now competing for booster doses, thus stretching the current supply of mRNA vaccines. Arcturus Therapeutics has developed two low-dose, self-amplifying mRNA vaccines, ARCT-154 and ARCT-165, that elicits robust neutralizing antibodies in non-human primates (NHPs) as a primary vaccination series and as a booster vaccination to Comirnaty® in humans. In NHPs, we found that ARCT-154 provides better coverage against SARS-CoV-2 variants with a glutamic acid at position 484 (e.g. alpha and delta) while ARCT-165 provides better coverage against variants with a change in this position (e.g. beta, gamma, mu). When this single amino acid is reverted to a glutamic acid in either beta or gamma strains, ARCT-154 provides better neutralizing titers. However, in the context of a booster dose in humans (NCT05037097), ARCT-154 provides robust humoral responses across all variants tested. Next generation self-amplifying mRNA vaccines may provide better coverage and at booster doses that are 6–10 times lower than those of currently authorized mRNA vaccines.